Hyaluronic acid-urea pharmaceutical compositions and uses

ABSTRACT

This invention includes a pharmaceutical composition including a pharmaceutically acceptable carrier, urea, and hyaluronic acid or a pharmaceutically salt thereof. The invention also includes a method of treating disease of the cutis which includes applying to cutis tissues in need of such treatment a therapeutically effective amount of a composition comprising a pharmaceutically acceptable carrier, urea, and hyaluronic acid or a pharmaceutically acceptable salt thereof, said disease having symptoms selected from the group consisting of inflammation, erythema, edema, papules, vesicles, macules, pustules, scaling, cracking, crusting, and lesions. The invention further includes methods for the treatment of psoriasis, eczema, dermatitis, herpetic conditions, acne, skin ulcers, genital herpes lesions and anorectal disease, which includes applying to tissues in need of such treatment a therapeutically effective amount of a composition including a pharmaceutically acceptable carrier, urea and hyaluronic acid or a pharmaceutically acceptable salt thereof.

This application is a divisional of Ser. No. 08/101,826, filed Aug. 4,1993.

BACKGROUND OF THE INVENTION

The present invention concerns pharmaceutical compositions which includeurea and hyaluronic acid or derivatives of hyaluronic acid. The presentinvention further concerns methods of treating disease of the cutis,anorectal epithelium and rectal mucosa employing the aforementionedcompositions. The treated disease of the cutis exhibits symptoms such aserythema, edema, inflammation, papules, vesicles, pustules, macules,scaling, crusting, cracking, and/or lesions. Such disease would includepsoriasis, eczema, dermatitis, herpetic conditions and acne. Disease ofthe anorectal epithelium and rectal mucosa exhibits symptoms such asinflammation, cracking, burning, irritation, tenderness, pain, sorenessand itching.

The hyaluronic acid-urea preparations are topically applied as skin,anorectal epithelium and anorectal mucosa bonding and adhesion agents,anti-inflammatory agents and bio-repair materials. The use of thehyaluronic acid-urea preparations reduce the inflammation, pain,itching, swelling, and sequelae of the skin, anorectal epithelium andrectal mucosa disease while adhering to and protecting the skin,anorectal epithelium and rectal mucosa tissues.

The composition of the present invention includes two principlecomponents: 1) hyaluronic acid and derivatives thereof; and 2) urea. Thederivatives of hyaluronic acid include any pharmaceutically acceptablesalt form, for example sodium hyaluronate.

The source of the hyaluronate used in the present pharmaceuticalcompositions may be a hyaluronic acid or any acceptable salt form ofhyaluronic acid. The term "hyaluronate" is often used to mean"hyaluronic acid equivalent" which equates to hyaluronic acid of varyingmolecular weights and any of their salt forms.

Hyaluronic acid is a naturally occurring mucopolysaccharide with amolecular weight generally ranging between about 50,000 and 8,000,000(or possibly higher), depending on the source of the material and theanalytical methods used in its determination.

Methods of obtaining highly-pure or ultra-pure hyaluronic acid and itssalt forms, isolation techniques, and analytical methods for testingpurity are provided, for example, in the U.S. Pat. Nos. 3,396,081,4,141,973, 4,517,295, 4,736,024, 4,784,900 and 4,808,576.

Hyaluronic acid is a linear mucopolysaccharide comprised of alternatingglucuronic acid and N-acetyl-glucosamine residues that interact withother proteoglycans to provide stability and elasticity to theextracellular matrix of all tissues. This network of macromoleculesregulates tissue hydration and the movement of substances within theinterstitial compartment. In resting states most hyaluronic acid iscross-linked with collagen and other high molecular-weight substances,so the concentration of free hyaluronic acid is relatively low.Concentrations of hyaluronic acid are dramatically elevated, however,immediately after tissue injury.

Hyaluronic acid is well known, being found in the joint tissue as wellas the vitreous humor of the eyes of mammals. It has been extracted fromrooster combs, human umbilical cords and bacterial cultures such asthose of hemolytic streptococci groups A and C for various therapeuticpurposes. One of the first therapeutic uses of this material was as areplacement for the liquid vitreous of the human eye to aid inophthalmic surgery, especially in the treatment of retinal detachment.It has also been used for the relief of trauma or irritation in jointtissue of mammals including humans by injection into the synovial fluidof the joint.

Hyaluronic acid and the various salt forms of hyaluronic acid havedemonstrated hydrating, lubricating, moisturizing, mechanical,cushioning and wound healing properties.

Commercial hyaluronic acid products, in the United States, include:Viscoat® (Alcon Surgical), Healon® (Pharmacia Opthalmics) and Amvisc®(Lolab).

The second principle component of the present pharmaceutical compositionis urea. Urea is represented by the molecular formula CH₄ N₂ O orCO(NH₂)₂. Urea has a molecular weight of 60.06, is freely soluble inwater, and has a melting point of 132.7°. Urea is used extensively inthe paper industry to soften cellulose. It is also used in fertilizers,animal feeds and ammoniated dentifrices.

Urea is a product of protein metabolism and is the chief nitrogenousconstituent of human urine. Urea is a protein denaturant that promoteshydration of keratin and mild keratolysis in dry and hyperkeratoticskin. It is used topically in the treatment of psoriasis, ichthyosis,atopic dermatitis and dry scaly conditions, usually in a 2% to 25% creamor lotion. Urea has long been used as an osmotic diuretic, to promotethe healing of infected wounds, and for its antiseptic value.

Commercial medical products containing urea, in the United States,include: Aquacare® (Menley and James), Nutraplus® (Owen/Galderma),Carmol 10®, Carmol 20® and Carmol HC® (Syntex), Gormel Creme® andGordon's Urea 40%® (GORDON), Lanaphilic® (Medco), Ureacin-10®,Ureacin-20® and Ureacin-40® (Pedinol) and Ultra Mide-25® (BakerCummins).

Embodiments of the present invention include pharmaceutical compositionscomprising urea in an amount of 0.1-40% by weight and hyaluronic acid orpharmaceutically acceptable salts thereof in an amount of 0.05-25% byweight. The compositions of the invention have been made and topicallyapplied to diseased cutis, anorectal epithelium and rectal mucosa tosuccessfully relieve burning, itching, tenderness, pain, soreness andother discomforts. The hyaluronic acid-urea compositions protect tissuesof the cutis, anorectal epithelium and rectal mucosa by adhering to themand helping to heal and alleviate disease symptoms.

SUMMARY OF THE INVENTION

The present invention includes compositions comprising urea andhyaluronic acid or its derivatives, and the use of such compositions. Inthe present compositions, each of hyaluronic acid (or derivatives) andurea is a pharmaceutically active agent. The compositions are used totreat disease of the cutis by topically applying to the cutis tissues, atherapeutically effective amount of the composition. The disease statesof the cutis include but are not limited to psoriasis, eczema,dermatitis, herpetic conditions, acne and more generally, disease of thecutis having symptoms of erythema, edema, inflammation, papules,vesicles, macules, pustules, scaling, cracking, crusting, and/orlesions.

The compositions are further used to treat disease of the anorectalepithelium and rectal mucosa by topically applying to such tissues, atherapeutically effective amount of the present compositions. Thedisease states of the anorectal epithelium and rectal mucosa include butare not limited to rectal fissures and pruritus ani and more generally,disease of the anorectal epithelium and rectal mucosa having symptoms ofinflammation, cracking, irritation, soreness, tenderness, burning, painand itching.

Accordingly, one important object of the present invention is to providepharmaceutical compositions which include urea and hyaluronic acid or anacceptable salt form of hyaluronic acid which have utility in treatingdisease of the cutis, anorectal epithelium and rectal mucosa.

Another important object of the present invention is to provide methodsfor protecting, and promoting the healing of and alleviating thesymptoms of diseased cutis, rectal epithelium and rectal mucosaincluding symptoms of erythema, edema, inflammation, papules, vesicles,macules, pustules, scaling, cracking, crusting and/or lesions, whilereducing the associated burning, itching, swelling, irritation, pain,soreness and general discomfort by means of the topical application ofthe hyaluronic acid-urea composition.

A related object of the present invention is to provide a method oftreating disease of the cutis, rectal epithelium and rectal mucosa byutilizing the advantageous bonding and adhering properties as well asthe anti-inflammatory, hydrating and healing properties of thehyaluronic acid-urea composition.

Significant Discussion

While a few therapeutic characteristics have been attributed tohyaluronic acid employed alone and urea employed alone, a completeunderstanding of their independent physiological effect, particularlywith respect to the cutis, rectal epithelium and rectal mucosa is notknown. Therapeutic compositions containing hyaluronic acid (orderivatives) and urea are not known. Certainly the therapeutic effect ofsuch compositions on disease of the cutis, rectal epithelium and rectalmucosa is not known.

In developing the present invention, clinical investigation has shownthat hyaluronic acid or urea aids the therapeutic effect of the other topromote the healing of and alleviate the symptoms of diseased cutis,rectal epithelium and rectal mucosa. In the present invention,hyaluronic acid (or derivatives) is an active pharmaceutical agent andurea is an active pharmaceutical agent. The combination of hyaluronicacid (or derivatives) and urea produces a coordinated or correlatedaction by the two agents resulting in their therapeutic effect beinggreater then the sum of the therapeutic effect of each agent takenseparately. Present clinical investigation has shown the active agentsof the present composition to have a synergistic therapeutic effect.

Thus, the present new combination of hyaluronic acid (or derivatives)and urea produces a surprisingly efficacious therapeutic effect in thetreatment of disease of the cutis, rectal epithelium and rectal mucosa.

DETAILED DESCRIPTION OF THE INVENTION AND SOME PREFERRED EMBODIMENTS

To accomplish some of the above described objects of the presentinvention, one embodiment of the invention is pharmaceuticalcompositions which include urea and hyaluronic acid or pharmaceuticallyacceptable salts thereof.

An embodiment of the present invention is the use of hyaluronic acid (orits salts) with urea to employ their combined therapeutic effects in thetreatment of disease of the cutis.

Another embodiment of the present invention is to employ the presentcompositions with particular respect to the property of hyaluronic acidand its derivatives to bond or strongly adhere to cutis tissues, inmethods of treatment which provide a protective coating on theirritated, inflamed, burning and/or itching tissues.

A further embodiment of the present invention is to employ the combinedtherapeutic effect of hyaluronic acid (or acceptable salts) and urea topromote the healing of disease of the cutis having symptoms of erythema,edema, papules, inflammation, vesicles, macules, scaling, pustules,cracking, crusting and lesions.

Additional embodiments of the present invention include: (1) treatmentof psoriasis; (2) treatment of eczema; (3) treatment of dermatitis; (4)treatment of herpetic conditions; (5) treatment of acne and (6)treatment of skin ulcers.

Another embodiment of the present invention includes the treatment ofdisease of the rectal epithelium and rectal mucosa including anorectaldisease having symptoms of cracking, inflammation, irritation, soreness,burning, tenderness, pain, and itching.

An important advantage of using hyaluronate for cutis treatment is thatwhile sodium hyaluronate, for example, may be compared to hydrocortisonein its anti-inflammatory effect, unlike hydrocortisone or otherglucocorticoids, sodium hyaluronate is not catabolic in nature.Hyaluronic acid and its derivatives enhance the anabolic process asopposed to the catabolic process.

Any pharmaceutically acceptable form of hyaluronic acid may be used inthe present invention. This application for the most part, however, willbe principally concerned with the representative use of the readilyavailable commercial forms of hyaluronate, such as hyaluronic acid, thepotassium salt of hyaluronic acid, and more preferably sodiumhyaluronate. This in no way limits the forms of hyaluronic acid employedin the present invention.

Hyaluronic acid (or derivatives thereof) and urea may be incorporatedinto numerous types of gels, creams, ointments, lotions, solids, pastes,salves, powders, liquids, sprays and/or aerosol vehicles. Steriledistilled water alone and simple cream, ointment and gel bases may beemployed as carriers of the hyaluronic acid and urea. Examples of basesand suspending vehicles include Fattibase™ (acrylic polymer resin base),Polybase™ (polyethylene glycol base) by Paddock Laboratories, Inc.,Minneapolis, Minn. Such pharmaceutically acceptable carriers are readilyavailable for preparing the present formulations and have desirablepH's, melting points, and preservatives.

Additional therapeutic agents may be added to the present formulationsas medically indicated, selected from the classes of: keratolytics,surfactants, counter-irritants, humectants, antiseptics, lubricants,astringents, wound healing agents, emulsifiers, wetting agents,additional adhesion/coating protectants, additional anti-inflammatoryagents, vasoconstrictors, vasodilators, anticholinergics,corticosteroids (e.g., glucocorticoids) and anesthetics. Preservativesand buffers may also be added.

In its more specific aspects, the present composition includes apharmaceutically acceptable carrier, urea in an amount of 0.1-40% byweight and hyaluronic acid (or pharmaceutically acceptable salt) in anamount of 0.05-25% by weight. The preferred amount of urea is 0.1-30% byweight and hyaluronic acid (or salt) is 0.05-15% by weight. The morepreferable amount is 0.5-30% by weight urea and 0.1-10% by weighthyaluronic acid (or salt). The most preferable amount is 1.0-25% byweight urea and 0.5-5.0% by weight hyaluronic acid (or salts). Theaforementioned amounts of hyaluronic acid (or salt) and urea aretherapeutically effective in the treatment of disease of the cutis,anorectal epithelium and rectal mucosa.

BRIEF DESCRIPTION OF THE DRAWINGS

Further objects and advantages of the present invention will be betterunderstood by carefully reading the following detailed description ofthe presently preferred exemplary embodiments in conjunction with theexamples and the accompanying drawings, of which:

FIG. 1 shows the results of infrared (IR) absorbance analysis of 1%hyaluronic acid;

FIG. 2 shows the results of infrared absorbance analysis of 1% sodiumhyaluronate (NaHy);

FIG. 3 shows the results of infrared absorbance analysis of 1% urea;

FIG. 4 shows the results of infrared absorbance analysis of a mixture of1% urea and 1% sodium hyaluronate after 30 minutes;

FIG. 5 shows the results of infrared absorbance analysis of a mixture of1% urea and 1% hyaluronic acid at 45 minutes;

FIG. 6 shows the superimposition of IR absorbance analysis resultsfor 1) 1% urea, 2) 1% hyaluronic acid and 3) 1% urea+1% hyaluronic acidmixture.

The invention is demonstrated with reference to the following examples,which are of an illustrative nature only and which are to be construedas non-limiting.

EXAMPLES INFRARED ABSORBANCE ANALYSIS OF HYALURONIC ACID, SODIUMHYALURONATE, UREA, AND COMBINATIONS

In order to gain a greater knowledge of the combination of hyaluronicacid (and acceptable salts) and urea of the present composition,infrared absorbance analyses were performed for 1) hyaluronic acid; 2)sodium hyaluronate; 3) urea; 4) urea combined with sodium hyaluronate;and 5) urea combined with hyaluronic acid. A comparison of the infraredabsorbance analysis of combined sodium hyaluronate or hyaluronic acidand urea with the infrared absorbance analysis of sodium hyaluronatealone or hyaluronic acid alone and urea alone help determine if a newcompound is formed by their combination.

A sample of 1% sodium hyaluronate was prepared by combining 0.3030 gramsof sodium hyaluronate, lot #1-9070-4, with 30.0011 grams ofwater-for-injection (WfI), lot 024052. The sample was mixed usingcoupled syringes. A sample of 1% hyaluronic acid was prepared by adding0.125 mls 0.1N HCl to 10 mls of the sodium hyaluronate, dropping the pHto 5.03 (i.e. pH 5.0). A sample of 1% Urea was prepared by adding 0.3333grams Urea to 30.0009 grams of WfI.

A sample of the sodium hyaluronate/urea combination was made by adding2.5 mls of each together. A sample of the hyaluronic acid/ureacombination was made by adding 2.5 mls of each together. The sampleswere mixed by coupled syringes.

The urea, sodium hyaluronate, hyaluronic acid, and sodiumhyaluronate/urea and hyaluronic acid/urea combinations were scanned forabsorbance using infrared spectroscopy. Graphs of the scan spectraresults are presented in FIGS. 1, 2, 3, 4, 5 and 6.

The infrared (IR) spectra of 1% urea, 1% sodium hyaluronate, 1%hyaluronate @ pH 5.0 (hyaluronic acid), urea+sodium hyaluronate mixtureand urea+hyaluronate @ pH 5.0 (hyaluronic acid) mixture provide thefollowing interpretations and conclusions.

FIGS. 1 and 2 respectively show IR spectra for 1% hyaluronic acid and 1%sodium hyaluronate (NaHy). The spectra for sodium hyaluronate andhyaluronic acid are essentially identical. Note that the 3383 cm-1 bandof OH stretches from numerous carboxylic acid and hydroxyl groups andwater from the solution. The 1621 cm-1 band is due to the carboxylateanion and water. This is an asymmetrical stretch. A weaker symmetricalstretching band for the same group is at 1417 cm⁻¹. The 1054.5 cm bandis a C--O stretch, ether type, of which there are many in hyaluronicacid.

FIG. 3 shows IR spectra for 1% urea. Note that the 3444.4 and 3354 cm⁻¹bands are the NH stretch for hydrogen bonded primary amide with possibleinterfering OH. The 1676.8 and 1614 cm⁻¹ bands are the carbonyl C-Ostretch with the amide 1 bands overlapping. Water absorbs at 1620 cm⁻¹and may have interfered here as well. The 1466-1444 cm⁻¹ band is theC--N stretch.

The IR spectrum of the mixtures clearly represents a physical mixture ofthe two substances. Each band in the mixture spectrum can be attributedto urea or sodium hyaluronate or hyaluronic acid as they appear in theirrespective IR spectra. Note that the doublet at 2400 cm⁻¹ is due toatmospheric carbon dioxide. This is experimental error which probablyresults from an insufficiently purged IR spectrometer prior to analysis.

FIG. 4 shows IR spectra for 1% urea plus 1% sodium hyaluronate. FIG. 5shows IR spectra for 1% urea plus 1% hyaluronic acid (hyaluronate @ pH5.0). A comparison of the spectra of FIG. 1 i.e., hyaluronic acid, FIG.3 i.e., urea and FIG. 5 i.e., urea plus hyaluronic acid clearly showsthat no chemical changes have occurred to the urea and hyaluronic acidwhen present in combination at the specified pH. A comparison of thespectra in FIG. 2 i.e., sodium hyaluronate, FIG. 3 i.e., urea and FIG. 4i.e., urea plus sodium hyaluronate shows that no chemical changes haveoccurred to the urea and sodium hyaluronate in combination at thespecified pH. FIG. 6 superimposes the spectra for urea, hyaluronic acidand hyaluronic acid plus urea to facilitate a direct comparison. FIG. 6helps to confirm the conclusion that no significant chemical change hasoccurred to the urea and hyaluronic acid when combined together in thecomposition of the present invention. No chemical reaction has occurredbetween the urea and hyaluronic acid or urea and sodium hyaluronate.

The fact that the combination of urea and hyaluronic acid (or its salts)do not react to form a new compound, supports the present findings thateach of the two pharmaceutically active agents aid the therapeuticeffect of each other or that one agent aids the therapeutic effect ofthe other.

EXEMPLARY COMPOSITIONS Compositions Of The Present Invention

The present hyaluronate-urea preparations may be formulated as a cream,lotion, gel, ointment, solid, paste, salve, powder, liquid, spray and/oraerosol, depending on the ingredients and the amounts employed.

In the following exemplary compositions of the present invention, allliquid measures were converted to the number of grams of liquid used.All solids were dissolved in the appropriate vehicle or melted prior tomixing and blending. All chemical manipulations were performed in alaminar air flow hood. All equipment contacting product or productpreparations were sterile and pyrogen free.

Example A

The following reagents and equipment were used for the preparation of abuffered, pH adjusted, preserved and fragrance added, 1.10% sodiumhyaluronate and 2.5% urea lotion:

37% Hydrochloric Acid

Water for Injection (WfI)

Sodium Hyaluronate

Benzyl Alcohol

Methyl Paraben

Sodium Propionate

Sodium Phosphate, Dibasic, Heptahydrate

Sodium Phosphate, Monobasic, Monohydrate

Urea

Fattibase, (Paddock Laboratories)

Glycerin USP

Lecithin

Polyethylene Glycol 4000

Soluble Rose Fluid Extract

Parafilm

Hot Plate

Stir Plate

Magnetic Stir Bar

Standard Laboratory Glassware

Highly Sensitive Balance

Nalgene Containers

pH Meter

Reagant Preparation: 1N HCl

1. A 1000 ml volumetric flask was filled with approximately 750 mls ofWater for Injection.

2. 96.2 grams of 37% HCl were added to the WfI in the volumetric flask.

Weight 96.39 gm

3. The flask was covered with parafilm.

4. The flask was inverted several times to mix the contents.

5. An appropriate quantity of WfI was added, sufficient to result in1,000 mls of solution.

Phosphate Buffered Solution

1. 22 grams of WfI were weighed and added to a beaker.

weight 22.0045 gm

2. 3.1372 grams of sodium phosphate dibasic, heptahydrate were weighedand added to the WfI.

weight 3.1371 gm

3. 7.8628 grams of sodium phosphate monobasic, monohydrate were weighedand added to the WfI.

weight 7.8626 gm

4. Using a stir plate and magnetic stir bar, the solution was mixeduntil the contents were dissolved (by visual inspection).

5. The solution pH was measured and recorded.

pH 5.02

If the solution pH was not 5.00±0.05, then a new phosphate bufferedsolution would have been made which would have a pH of 5.00±0.05 using20 grams of WfI and 10 grams total of phosphates.

Sodium Propionate Solution

1. 22.0 grams of WfI were weighed and added to a beaker.

weight 22.0101 gm

2. 20.944 grams of sodium propionate were weighed and added to the WfI.

weight 20.9441 gm

3. Using a stir plate and magnetic stir bar, the solution was mixeduntil the contents were dissolved (by visual inspection).

pH 9.35

Urea Solution

1. 25.0 grams of WfI were weighed and added to a beaker.

weight 25.0018 gm

2. 25.0 grams of urea were weighed and added to the WfI.

weight 25.0012 gm

3. Using a stir plate and magnetic stir bar the solution was mixed untilthe contents were dissolved (by visual inspection).

pH 7.43

Lotion Base Water-in-Oil Emulsion

1. 45.0 grams of fattibase, a homogenous blend of trigylcerides fromPalm, Palm Kernel and coconut oils (by Paddock Laboratories), wereweighed and added to a beaker.

weight 45.0011 gm

2. 15.0 grams of PEG 4000 were weighed and added to the fattibase,.

weight 15.0001 gm

3. 15 grams of Glycerine USP were weighed and added to the same beaker.

4. 15.0 grams of Lecithin were weighed and added to the fattibase,,glycerin and PEG4000.

weight 15.0102 gm

5. 39.0 grams of Soluble Rose Fluid Extract were weighed and added tothe beaker.

weight 39.0120 gm

6. The above ingredients were gently heated on a hot plate to atemperature of not more than 56° C.

7. Using a glass stirring rod, the contents were mixed until all theingredients melted.

8. The contents were allowed to cool to room temperature with continuousstirring until a firm, stable water-in-oil emulsion resulted.

Procedure

1. 660 grams of WfI were weighed and added to a 2 liter beaker.

weight 660.0 gm pH 6.53

2. 22 grams of benzyl alcohol were weighed and added to the beaker.

weight 22.0400 gm

3. Using a stir plate and magnetic stir bar, the solution was mixeduntil the contents were dissolved (by visual inspection).

pH 6.10

4. 1.65 grams of methylparaben were weighed and added to the beaker.

weight 1.6498 gm

5. Using a stir plate and magnetic stir bar, the solution was mixeduntil the contents were dissolved (by visual inspection).

pH 4.40

6. 50.0 grams of urea solution were added to the beaker.

7. Using a stir plate and magnetic stir bar, the combined solutions werethoroughly mixed.

8. 11.0 grams of sodium hyaluronate were weighed and added to thebeaker.

weight 11.0014 gm

9. Using a stir plate and magnetic stir bar, the solution was mixeduntil the contents were dissolved (by visual inspection). This step wasperformed overnight. The mixing start and stop times were recorded.

pH 5.60

10. The solution pH was adjusted to 3.1±0.05 using 1N HCl. The amount of1N HCl used was recorded (in grams) and the final pH was recorded.

weight 17.1637 gm pH 3.11

11. The solution pH was adjusted to 5.0±0.09 using the sodium propionatesolution. The amount of sodium propionate used was recorded (in grams)and the final pH was recorded.

weight 7.0847 gm pH 4.95

12. The phosphate buffer solution was added to the beaker.

13. A stir plate and magnetic stir bar were used to mix the solutionuntil the contents were dissolved and well mixed (by visual inspection).

pH 5.54

14. An appropriate weight of WfI and 1N HCl were added to result in 871grams of solution and a pH of 5.0±0.09. The weight of the WfI and HClwere recorded and the pH was recorded.

    ______________________________________                                        weight WfI        62.056       gm                                             weight 1 N HCl    7.06741      gm                                             pH                5.08                                                        Total weight of Solution                                                                        871.06       gm                                             ______________________________________                                    

15. A hot plate was used to heat the water-in-oil emulsion to a slurry.This slurry was added to the solution, and thoroughly mixed and blended.This resulted in one liter of a buffered, preserved, fragranced and pHadjusted 1.1% sodium hyaluronate and 2.5% urea lotion.

Note that the same or similar methodology of preparation, as set forthin above Example A), was employed in the following compositions ofExamples B)-E). Furthermore, numerous preservative, buffering andfragrance systems are readily available and this disclosure is notlimited to those mentioned herein. Creams, ointments, lotions,solutions, gels, pastes, salves and spray dosage forms may be derived byvarying the amounts of waxes, solids, fats, greases, oils and liquidsused in a particular formulation.

Example B

A 15% sodium hyaluronate and 40% urea highly viscous gel was made by thefollowing method.

1. 45 gm WfI were weighed and added to a beaker

2. 40 gm of urea were weighed and added to the WfI.

3. The contents were thoroughly mixed and dissolved (by visualinspection).

4. 15 gm of sodium hyaluronate were weighed and added to the beaker.

5. The contents were mixed overnight and dissolved (by visualinspection).

6. This resulted in 100 gm of a 15% sodium hyaluronate/40% urea gel.

Example C

A 40% urea and 0.05% sodium hyaluronate gel was made as follows:

1. 58.95 gm of WfI were weighed and added to a beaker.

2. 40.00 gm of urea were weighed and added to the WfI.

3. The contents were mixed and dissolved (by visual inspection).

4. 0.05 gm (50mg) of sodium hyaluronate were weighed and added to thebeaker.

5. The contents were thoroughly mixed and dissolved (by visualinspection).

6. 1.0 gm carbopol 940 was weighed and added to the beaker.

7. The solution was mixed until the contents were dissolved (by visualinspection).

8. This resulted in 100 gm of a 40% urea/0.05% sodium hyaluronate gel.

Example D

A 15% sodium hyaluronate and 0.1% urea cream was prepared as follows:

1. 75.90 gm of WfI was weighed and added to a beaker.

2. 0.10 gm of urea (100 mg) were weighed and added to the WfI and mixedwell.

3. 15 gm of sodium hyaluronate were weighed and added to the beaker. Thecontents were mixed overnight until dissolved (by visual inspection).

4. In a separate beaker 4.5 gm fattibase,, 1.5 gm glycerin, 1.5 gmlecithin and 1.5 gm PEG4000 were mixed, melted and then added to thefirst beaker.

5. The contents of both beakers were thoroughly mixed until wellblended. This resulted in a stiff cream formulation.

Example E

A dilute 0.05% sodium hyaluronate and 0.1% urea cream was made asfollows:

1. 84.85 gm WfI were weighed and added to a beaker.

2. 0.1 gm (100 mg) of urea were weighed and added to the WfI.

3. The above were thoroughly mixed.

4. 0.05 gm (50 mg) of sodium hyaluronate were weighed and added to thesolution.

5. The above were mixed until dissolved (by visual inspection).

6. 1.5 gm Carbopol 940 were weighed and added to the solution.

7. The above solution was mixed until the contents were dissolved (byvisual inspection).

8. 6.75 gm of fattibase,, 2.25 gm Lecithin, 2.25 gm Glycerin and 2.25 gmPEG4000 were weighed and added to a separate (second) beaker.

9. The above contents of the second beaker were heated to 55° C.

10. The above contents of the second beaker were continuously melted andstirred to form a slurry.

11. The resulting slurry was added to the solution.

12. The combined contents of both beakers were thoroughly mixed andblended (by visual inspection).

13. This resulted in 100 gm of a 0.05% sodium hyaluronate and 0.1% ureacream formulation.

Example F

A 1.5% hyaluronate and a 12% urea cream formulation with preservativeswas prepared as follows:

    ______________________________________                                        1.    dissolve: 2.5 gm   benzyl alcohol in 70 gm H.sub.2 O                          add       5.0 gm   sodium propionate                                          add       12.0 gm  urea                                                       mix & dslv.                                                                             1.5 gm   sodium hyaluronate                                         Subtotal =                                                                              91.0 gm                                                       ______________________________________                                    

2. Next, heat, melt and mix:

5.0 gm fattibase®

1.5 gm glycerin U.S.P

1.5 gm PEG 4000

1.0 gm Lecithin

3. Add the mixture of step 2 to the solution of above step 1.

4. Results=100 gm 1.5% sodium hyaluronate and 12% urea cream(preparation≦preservatives).

Example G

A 100 gm sample of a 2.0% urea and a 2.0% hyaluronate lotion wasprepared as follows:

2 gm sodium hyaluronate

2 gm urea

4.5 gm fattibase®+87 gm H₂ O

1.5 gm lecithin

1.5 gm glycerine

1.5 gm PEG 4000

Results=100.00 gm 2% lotion.

Example H

A 1% hyaluronate and 10% urea cream formulation was prepared as follows.

1 gm NaHy

10 gm Urea

4.5 gm fattibase®

1.0 gm lecithin

1.5 gm glycerin

2.0 gm PEG 4000

80.0 gm H₂ O

Example I

Urea/sodium hyaluronate preparations may generally be made by addingsodium hyaluronate to a simple urea solution, such as in the followingReference Example VIII. Deduct the number of grams of water for theamount of hyaluronate (grams) to be added. This can be converted intocreams, lotions or gels by following the previously mentioned methods.Preservatives and buffer systems may also be added (there are numerouspreservatives and buffer systems available for this purpose).

Reference Compositions Reference Example I

A viscous aqueous solution of hyaluronic acid, or salt thereof, with gelproperties, was prepared by dissolving 5.0% hyaluronate in water.Example:

    ______________________________________                                         95.00 gm   H.sub.2 O                                                          5.00 gm    Sodium Hyaluronate                                                100.00 gm   Total = 5% hyaluronate viscous                                                solution.                                                         ______________________________________                                    

Reference Example II

In order to enhance gel properties, carbopol, or carbomer, may be added.Preservatives may also be added. Such a formulation was preparedpursuant to the following example:

    ______________________________________                                                  94.00 gm  H.sub.2 O                                                           1.00 gm   Carbopol 940                                                        4.00 gm   Sodium Hyaluronate                                                  0.20 gm   methylparaben                                                       0.10 gm   propylparaben                                                       0.70 gm   et. alc. = 4% hyaluronate gel                             Total =   100 gm                                                              ______________________________________                                    

Reference Example III

A dilute preparation of hyaluronic acid, or salt thereof, was madepursuant to the following example:

    ______________________________________                                                  99.90 gm  H.sub.2 OI                                                          .10 gm    Sodium hyaluronate                                        Total     100.00 gm 0.1% Sodium hyaluronate                                                       preparation.                                              ______________________________________                                    

Reference Example IV

In general, hyaluronic acid preparations may be made by adjusting the pH(e.g. of sodium hyaluronate). Mineral acids like hydrochloric acid arequite suitable for this purpose and make it relatively easy to achievethe desired pH. Buffer systems may be employed to preserve and protectthe desired pH. Sodium phosphate monobasic monohydrate and sodiumphosphate dibasic heptahydrate work quite well for this purpose. Sodiumpropionate and benzyl alcohol are suitable preservatives for this typeof preparation.

    ______________________________________                                                   80.0 gm  H.sub.2 O                                                            6.0 gm   sodium hyaluronate                                        subtotal   86.0 gm  qs ≦ Hcl to desired pH                                                 qs ≦ H.sub.2 O to 100 gm                           Result =   100.0 gm of 6.0% hyaluronic acid                                                       formulation.                                              ______________________________________                                    

Reference Example V

A 20.0% hyaluronate preparation was made by dissolving 20 gm of sodiumhyaluronate in 80 gm of water at room temperature (more than 24 hoursmay be required to dissolve the hyaluronate).

Reference Example VI

A 10% Urea solution was made by dissolving 10% Urea in water. Example:

    ______________________________________                                        10.0 gm      Urea                                                             90.0 gm      water                                                            100.0 gm     total - 10% Urea Solution.                                       ______________________________________                                    

Reference Example VII

A 20% urea lotion was prepared by:

1. mixing, heating, and melting

4.50 gm fattibase®

1.50 gm glycerin (U.S.P)

1.50 gm PEG -4000

1.50 gm Lecithin

2. Adding the above to a solution of 20 gm of urea dissolved in 71 gm ofwater.

Resulting total=100.00 gm of a 20.0.% urea lotion.

Reference Example VIII

A 40% urea solution .was made by dissolving 40 gm of urea in 60 gm of H₂O

Result=100 gm of 40% urea solution.

Numerous formulations may be derived by varying the concentrations ofthe above mentioned ingredients of the above examples and may bedetermined by the desired characteristics of the finished products. Itshould also be remembered that other vehicle systems are available forthis purpose and therefore this disclosure is not limited to theexamples provided.

CLINICAL EVALUATIONS REFERENCE CLINICAL EVALUATION

A baseline was established setting forth the therapeutic effect ofemploying a composition containing sodium hyaluronate as the solepharmaceutically active agent for treatment of disease of the cutis, byperforming the following clinical study.

Psoriasis is a chronic skin disorder which affects many patients seen ina dermatologic practice. This study was conducted to determine theefficacy of sodium hyaluronate in the treatment of patients with plaguetype psoriasis vulgaris.

METHODS

Fifteen patients participated in this study, each with plague typepsoriasis vulgaris. The patients were asked to apply a sodiumhyaluronate cream by itself, without other treatment, twice daily toskin lesions. The cream contained 2.0% by weight sodium hyaluronate. Theextent of severity of disease ranged from 15% to 40% (rule of nines).This corresponds to body surface area involved. The patients wereevaluated at weeks 1 and 2 of treatment as to the extent of improvement.Patients were graded on a scale of 0-4 by the same physician at eachtreatment visit.

RESULTS

As can be seen by the results shown in Table 1, the effect of the sodiumhyaluronate varied from no improvement to moderate improvement (25-50%).Improvement was determined by decrease in redness, scale and thicknessof psoriatic lesions. At week 1, the mean improvement level was 0.6. Atweek 2 the mean improvement level was 0.53 (see scale of improvement onTable 1). At week-2, two patients showed moderate improvement, fourpatients showed minimal improvement and nine patients showed noimprovement. No adverse reactions were noted by the patients.

                  TABLE 1                                                         ______________________________________                                        RESULTS: PSORIASIS VULGARIS                                                   Patient                                                                             Initial Body % Involved                                                                          Week 1   Week 2                                      ______________________________________                                        1)    25                 0        0                                           2)    40                 0        0                                           3)    30                 1        0                                           4)    25                 1        1                                           5)    15                 0        0                                           6)    20                 2        1                                           7)    10                 0        1                                           8)    15                 1        0                                           9)    35                 0        0                                           10)   40                 2        2                                           11)   25                 0        0                                           12)   30                 0        1                                           13)   20                 1        0                                           14)   15                 1        2                                           15)   25                 0        0                                           ______________________________________                                         2% Sodium Hyaluronate Cream in Treatment of Psoriasis                         Degree of Improvement                                                         0 = No Improvement                                                            1 = Minimal 1-25%                                                             2 = Moderate 25-50%                                                           3 = Good 50-75%                                                               4 = Excellent 75%+-                                                      

CLINICAL EVALUATIONS OF PRESENT INVENTION CLINICAL EVALUATION-1

Common skin disorders such as psoriasis, eczema, contact dermatitis andherpetic conditions are seen routinely in a dermatologic office setting.Normally, these conditions have been treated with various topicalmedications including topical corticosteroids, topical acyclovir andsometimes internal medications such as oral corticosteroids. Patientsalso tend to treat skin lesions with many over-the-counter medicationssuch as Benadryl cream and Cortaid.

The following was a double-blinded study of 1) hyaluronic acid, 2) ureaand 3) combination of sodium hyaluronate with urea in the treatment ofvarious skin disorders.

METHODS

This study entailed 11 patients with a blistering or vesicular type ofdermatitis, 8 patients with an eczematous dermatitis and 10 patientswith psoriasis. The patients were treated in a double-blinded fashionwith either a cream containing (1) 1% sodium hyaluronate plus 4.5% urea,(2) 4.5% urea or (3) 2% hyaluronic acid. The patients were evaluated atweeks 0, 1, 2 and 4 and evaluated as to level of improvement. Level ofimprovement was evaluated by the same physician (LRF) as to none equals0, 1 equals minimal or 0 to 25 percent improvement, 2 equals moderate or25 to 50 percent improvement, 3 equals good or 50 to 75 percentimprovement or 4 equals excellent which is greater than 75 percentimprovement. The patients were told to use the medication twice dailyand to contact the physician if any adverse reactions were noted. At theend of the study period the results were compiled.

RESULTS

The patient results are broken down into three categories. In thevesicular (contact) dermatitis component of the treatment 11 patientswere treated. Of these 11 patients 3 were treated with urea, 4 weretreated with the combination of sodium hyaluronate plus urea and 3 weretreated with urea alone. By week 2 the combination of sodium hyaluronateplus urea had caused the patients to improve between good to excellent.The patients treated with urea improved minimally and the patientstreated with hyaluronic acid improved moderately. (See Table 2 and 3)

In the eczema group, 2 of the patients were treated with urea, 3 of thepatients were treated with sodium hyaluronate plus urea and 3 weretreated with hyaluronic acid. In this group, by week 4, the patientstreated with urea had improved moderately. The patients treated withHyaluronic acid had improved minimally and the patients treated with thecombination had improved moderately. (Table 4 and 5)

In the psoriasis group 10 patients were treated; 3 with urea, 3 with thecombination medication of sodium hyaluronate with urea and 4 withhyaluronic acid. In this study the urea patients showed minimalimprovement, the combination showed minimal improvement and thehyaluronic acid patients showed no improvement at week 4. (See Table 6and 7)

                  TABLE 2                                                         ______________________________________                                        RESULTS: CONTACT DERMATITIS (Vesicular)                                       Patients                                                                              Week 1   Week 2   Week 4 Code                                         ______________________________________                                        1)      1        2        N/A    HA                                           2)      2        3        N/A    NAHA + Urea                                  3)      2        3        N/A    U                                            4)      3        4        N/A    NAHA + Urea                                  5)      1        3        N/A    HA                                           6)      2        3        N/A    NAHA + Urea                                  7)      1        3        N/A    HA                                           8)      1        1        N/A    U                                            9)      2        4        N/A    NAHA + Urea                                  10)     0        1        N/A    U                                            11)     1        3        N/A    HA                                           ______________________________________                                         Scale                                                                         0  None                                                                       1  Minimal 0-25                                                               2  Moderate 25-50                                                             3  Good 50-75                                                                 4  Excellent 75+-                                                             HA = Hyaluronic Acid                                                          NAHA = Sodium Hyaluronate                                                     U = Urea                                                                 

                  TABLE 3                                                         ______________________________________                                        RESULTS: CONTACT DERMATITIS (Vesicular)                                       MEAN VALUES                                                                   Week    U           HA     NAHA + Urea-                                       ______________________________________                                        1)      1           1      2.25                                               2)      1.67        2.75   3.5                                                ______________________________________                                         Scale                                                                         0  None                                                                       1  Minimal 0-25                                                               2  Moderate 25-50                                                             3  Good 50-75                                                                 4  Excellent 75+-                                                             HA = Hyaluronic Acid                                                          NAHA = Sodium Hyaluronate                                                     U = Urea                                                                 

                  TABLE 4                                                         ______________________________________                                        RESULTS: ECZEMA                                                               Patients                                                                              Week 1   Week 2   Week 4 Code                                         ______________________________________                                        1)      1        2        2      NAHA + Urea                                  2)      2        2        3      NAHA + Urea                                  3)      1        0        0      HA                                           4)      1        1        2      U                                            5)      2        1        2      U                                            6)      1        2        1      HA                                           7)      0        1        2      NAHA + Urea                                  8)      0        1        1      HA                                           ______________________________________                                         Scale                                                                         0  None                                                                       1  Minimal 0-25                                                               2  Moderate 25-50                                                             3  Good 50-75                                                                 4  Excellent 75+-                                                             HA = Hyaluronic Acid                                                          NAHA = Sodium Hyaluronate                                                     U = Urea                                                                 

                  TABLE 5                                                         ______________________________________                                        RESULTS: ECZEMA MEAN VALUES                                                   Week    U           HA     NAHA + Urea                                        ______________________________________                                        1)        1.5       0.67   1                                                  2)      1           1      1.67                                               4)      2           0.67   2.33                                               ______________________________________                                         Scale                                                                         0  None                                                                       1  Minimal 0-25                                                               2  Moderate 25-50                                                             3  Good 50-75                                                                 4  Excellent 75+-                                                             HA = Hyaluronic Acid                                                          NAHA = Sodium Hyaluronate                                                     U = Urea                                                                 

                  TABLE 6                                                         ______________________________________                                        RESULTS: PSORIASIS                                                            Patients                                                                              Week 1   Week 2   Week 4 Code                                         ______________________________________                                        1)      0        1        0      HA                                           2)      0        1        1      U                                            3)      1        1        1      U                                            4)      1        0        0      HA                                           5)      0        0        1      NAHA + Urea                                  6)      0        0        0      HA                                           7)      0        1        2      U                                            8)      0        1        0      HA                                           9)      1        2        2      NAHA + Urea                                  10)     1        1        0      NAHA + Urea                                  ______________________________________                                         Scale                                                                         0  None                                                                       1  Minimal 0-25                                                               2  Moderate 25-50                                                             3  Good 50-75                                                                 4  Excellent 75+-                                                             HA = Hyaluronic Acid                                                          NAHA = Sodium Hyaluronate                                                     U = Urea                                                                 

                  TABLE 7                                                         ______________________________________                                        RESULTS: PSORIASIS MEAN VALUES                                                Week    U           HA     NAHA + Urea                                        ______________________________________                                        1)      .33         0.25   .67                                                2)      1           .5     1                                                  3)      1.33        0      1                                                  ______________________________________                                         Scale                                                                         0  None                                                                       1  Minimal 0-25                                                               2  Moderate 25-50                                                             3  Good 50-75                                                                 4  Excellent 75+-                                                             HA = Hyaluronic Acid                                                          NAHA = Sodium Hyaluronate                                                     U = Urea                                                                 

Note: the only statistically significant difference was in the vesiculargroup between the patients treated with the combination of sodiumhyaluronate plus urea versus the patients treated with urea alone.Sodium hyaluronate would be useful in the treatment of such vesiculardiseases as herpes simplex.

Table 3 shows the mean values of level of improvement for treatingcontact dermatitis employing urea, hyaluronic acid and combined sodiumhyaluronate plus urea for the present study. Using the information inTable 3, the calculated mean level of improvement for urea for bothweeks 1 and 2 is 1.33, the mean improvement for hyaluronic acid overweeks 1 and 2 is 1.87 and the mean improvement for combined sodiumhyaluronate plus urea over weeks 1 and 2 is 2.87. The combination sodiumhyaluronate plus urea shows a 116% increase of effectiveness over ureaalone and a 53% increase of effectiveness over hyaluronic acid alone intreating contact dermatitis. The mean level of improvement for values ofboth urea and hyaluronic acid over the two week period is calculated tobe 1.6. The combination of sodium hyaluronate plus urea over two weeks(mean value=2.87) shows a 79% increase in level of improvement over thetwo week mean level of improvement for urea and hyaluronic acid (1.6).

Synergism is a phenomenon in which a mixture of two drugs exerts atherapeutic effect which is 1) greater than that exerted by the moreactive drug acting alone or 2) greater than the additive effect of thetwo drugs acting independently. The therapeutic effect of sodiumhyaluronate is assumed to be equivalent to that of the hyaluronic acidfor purposes of this consideration. Based on the foregoing calculations,the combination of sodium hyaluronate plus urea shows a significantlyhigher level of improvement compared to levels of improvement fromemploying urea and hyaluronic acid alone and compared to the meancombined level of improvement for urea and hyaluronic acid. Thisanalysis provides evidence of synergistic action by the sodiumhyaluronate plus urea composition in treating contact dermatitis.

Based on the mean levels of improvement for treating eczema shown inTable 4, the mean level of improvement for urea over weeks 1-4 is 1.5,the mean level of improvement for hyaluronic acid over weeks 1-4 is 0.78and the mean level of improvement for combined sodium hyaluronate plusurea over weeks 1-4 is 1.66. The mean level of improvement for combinedsodium hyaluronate plus urea is 11% greater then the mean level ofimprovement for urea alone. The mean level of combined sodiumhyaluronate plus urea is 113% greater then the mean level of improvementfor hyaluronic acid alone. The calculated mean level of improvement forboth urea and hyaluronic acid over weeks 1-4 is 1.14. The mean level ofimprovement for sodium hyaluronate plus urea (1.66) is 46% greater themean level of improvement for both urea and hyaluronic acid over weeks1-4 (1.14). The mean level of improvement of combined sodium hyaluronateplus urea over urea alone and hyaluronic acid alone falls within thedefinition of synergism as does the level of improvement of combinedsodium hyaluronate plus urea over the mean value of urea and hyaluronicacid levels taken together.

Based on the mean values of Table 7 (showing mean values of urea,hyaluronic acid and sodium hyaluronate and combined sodium hyaluronateplus urea in treating psoriasis), the calculated mean value for ureaover weeks 1-3 is 0.87, the mean value for hyaluronic acid for weeks 1-3is 0.25 and the mean value for combined sodium hyaluronate plus ureaover weeks 1-3 is 0.89. The mean value of sodium hyaluronate plus ureaover 3 the weeks is 2% greater then the mean value for urea over the 3weeks. The mean value of sodium hyaluronate plus urea over the 3 weeksis 256% greater then the mean value of the sodium hyaluronate over the 3weeks. The mean level of improvement for both urea and hyaluronic acidover the 3 week period is 0.56. The mean value for sodium hyaluronateplus urea over the 3 weeks is 59% greater then the mean value of ureaand hyaluronic acid over the 3 week period. These values show evidenceof synergism for the therapeutic effect of combined sodium hyaluronateplus urea.

CLINICAL EVALUATION -2

In the present study compositions containing sodium hyaluronate plusurea (NAHA+UREA) were employed in the treatment of lesions of herpessimplex, psoriasis vulgaris and eczematous dermatitis. The results werecompared with the effect of employing compositions containing generic 1%hydrocortisone cream (Revco brand). The purpose of this study was to seeif sodium hyaluronate plus urea was more, equal or less efficacious thanthe widely used over-the-counter medication, hydrocortisone, for thetreatment of common dermatologic disorders.

METHODS

In this study the patients were enrolled with paired skin lesions whichwere similar in appearance. Two patients with herpes simplex labialis,four patients with eczematous dermatitis, five patients with psoriasisvulgaris were treated in this open label study. For each patient onelesion was treated with 1% NAHA+10% Urea and a similar lesion wastreated with 1% Hydrocortisone cream. The patients were evaluated at thebeginning of the study and then re-evaluated after two weeks of therapy.The patients were graded initially as to the severity of the disease andthen at week two they were graded as to the degree of improvement. Thepatients were evaluated by the same physician at all visits (LFR). Thepatients were told to apply the appropriate medication to each lesiontwice daily and to notify the physician if any adverse reactionoccurred. At the end of the study the results were tabulated.

RESULTS

The patients' results are broken down according to the variousdermatologic conditions. In the herpes simplex group two patients withpaired lesions were treated. By week two, one of the lesions treatedwith NAHA+Urea had cleared and the other showed only an escharformation. This was considered marked improvement (See Table 8). In thepsoriasis group, two of the five lesions treated with NAHA+Urea showedmoderate improvement as compared to similar lesions treated with 1%Hydrocortisone which showed minimal improvement (See Table 9). In theeczematous group of lesions, two of the four lesions treated withNAHA+Urea showed moderate improvement as compared to similar lesionstreated with 1% Hydrocortisone cream which showed only minimalimprovement. (See Table 10)

In this study, it appears that NAHA+Urea was more effective than generic1% Hydrocortisone cream. Of great significance is the possiblesynergistic effect of sodium hyaluronate plus Urea. This may account forthe marked improvement in the herpes simplex lesions (vesicular).

The synergism might also account for a decrease in hyperkeratotic scaleseen in such conditions as psoriasis vulgaris and eczematous dermatitis.This may explain the superior results obtained using the combination ofsodium hyaluronate plus urea.

                  TABLE 8                                                         ______________________________________                                        RESULTS: HERPES SIMPLEX                                                       Patient                 Week 0   Week 2                                       ______________________________________                                        1)       NAHA + UREA    4        1                                                     1% HC cream    4        2                                            2)       NAHA + UREA    4        2                                                     1% HC cream    4        3                                            ______________________________________                                         Week 0 & 2 Evaluation                                                         4) Red Grouped Blisters                                                       3) Red Swollen Skin                                                           2) Crusted Eschar                                                             1) ClearedNormal Skin                                                    

                  TABLE 9                                                         ______________________________________                                        RESULTS: PSORIASIS VULGARIS                                                   Patient                 Week 0   Week 2                                       ______________________________________                                        1)       NAHA + UREA    Mod.     2                                                     1% HC cream    Mod      0                                            2)       NAHA + UREA    Min.     1                                                     1% HC cream    Min.     0                                            3)       NAHA + UREA    Severe   1                                                     1% HC cream    Severe   1                                            4)       NAHA + UREA    Mod.     0                                                     1% HC cream    Mod.     0                                            5)       NAHA + UREA    Mod.     2                                                     1% HC cream    Mod.     1                                            ______________________________________                                         Week 0 Evaluation                                                             Severe  Red Thick Scale                                                       Moderate  Red Plaque/Minimal Scale                                            Minimal  Red Skin/No Irritation                                               Degree of Improvement                                                         0) No Improvement                                                             1) Minimal 1-25%                                                              2) Moderate 25-50%                                                            3) Good 50-75%                                                                4) Excellent 75%+-                                                       

                  TABLE 10                                                        ______________________________________                                        RESULTS: ECZEMATOUS DERMATITIS                                                Patient                 Week 0   Week 2                                       ______________________________________                                        1)       NAHA + UREA    Mod.     2                                                     1% HC cream    Mod      1                                            2)       NAHA + UREA    Min.     1                                                     1% HC cream    Min.     1                                            3)       NAHA + UREA    Min.     2                                                     1% HC cream    Min.     0                                            4)       NAHA + UREA    Mod.     0                                                     1% HC cream    Mod.     1                                            ______________________________________                                         Week 0 Evaluation                                                             Severe  Red, Edematous, Micro Vesicles                                        Moderate  Red Scaly Patch                                                     Minimal  Redness with Scale                                                   Degree of Improvement                                                         0) No Improvement                                                             1) Minimal 1-25%                                                              2) Moderate 25-50%                                                            3) Good 50-75%                                                                4) Excellent 75%+-                                                       

CLINICAL EVALUATION - 3

A 70 year old female with fragile aging skin was suffering from arecalcitrant skin tear of the right thigh. The wound was treated formore than one month using conventional therapy which consisted of: dailycleansing and irrigation, oral and topical antibiotics and regulardressing changes. By the end of the fifth week, day #35, there was nonoted improvement.

Beginning on day #36, treatment with a composition containing 0.1%sodium hyaluronate and 1.0% urea was started. This cream preparation wasapplied to the skin tear three times a day for five consecutive days. Atthe end of the treatment on the 41st day, minimal improvement was noted.The application of a new formulation comprised of a 0.5% sodiumhyaluronate and a 5.0% urea concentration was started on the 42nd day.This second cream formulation was applied to the wound four times a dayfor one week. The skin tear was completely healed in seven days; 49thday of investigation.

CLINICAL EVALUATION -4

A relatively healthy 65 year old female had periodic scaling, itchingand peeling of the little and ring fingers of the left hand and scaling,itching and peeling of the middle and index fingers of the right hand.The problem was diagnosed as an allergic dermatitis of unknown etiology:possibly of contact or food origin. The periodic outbreaks, whichtypically last two to three weeks, were treated with various topicalsteroids over a period of several years with moderate to good success.

During one episode the patient applied a 0.05% sodium hyaluronate lotionformulation three to four times a day to the fingers of the left handand a 2.0% urea lotion formulation to the fingers of the right hand forfive consecutive days. At the end of the fifth day, the results wereinconsequential; no improvement or relief from itching was noted. A newformula combining 0.05% sodium hyaluronate and 2.0% urea was started onthe six day. Again, this new formula was applied three to four times aday for five more days. Accelerated healing was not demonstrated by theend of the 10th day. However, relief from itching was noted almostimmediately after the first application.

Several months later following another outbreak, a 1.5% sodiumhyaluronate and a 6.0% urea cream formulation was applied to theaffected fingers of both hands three to four times a day. Relief fromitching was immediate and dramatic improvement was noted by the thirdday of treatment. Scaling and peeling had ceased and by the fifth daythe affected fingers on both hands appeared almost completely normal.

CLINICAL EVALUATION -5

A 78 year old male had a condition in which the skin of both hands wasdry, cracked, split and had scale formation; a condition which occuredmost frequently during the winter months.

During one typical episode, a 20.0% sodium hyaluronate and a 25.0% ureacream formulation was applied three times a day to both hands. Thisformulation intensely aggravated the problem. Excessive dehydration andkeratolysis was obvious and, thus, the formulation was changed on thesecond day of treatment. The application of a 10.0% sodium hyaluronategel formulation, without any urea was instituted on the second day ofthis study. This second gel formulation also produced a drying,dehydrating effect and therapy with this formulation was terminated intwo days.

On day five of this investigation, treatment with a 2.0% sodiumhyaluronate and 12.0% urea cream formulation was initiated. This 2%/12%cream preparation was applied to the hands three times a day for nineconsecutive days. By the ninth day of treatment with this formulation,or the 14th day of the study, both hands appeared extremely wellhydrated, softened without scales, significantly improved withdiminished cracking and splitting and appeared, overall, well healed. Atthis point in time, the condition was 90.0% resolved.

CLINICAL EVALUATION -6

A 40 year old woman was taking the drug Accutane® for the treatment ofcystic acne. 80% of the cystic acne population treated with Accutane®experience dry, fragile, pruritic skin, a common adverse side effect. Toameliorate this condition, the woman was put on a regimen of applying acombined 2% hyaluronic acid and 15% urea cream formulation, buffered toa slightly acidic pH, three times a day. This 2%/15% formulation greatlyreduced the Accutane® induced side effects and proved superior to atleast six other commercial products used previously for the relief ofthis condition.

CLINICAL EVALUATION -7

A 64 year old woman with eczema over the entire body used a 20.0% ureacream preparation, a 2.0% sodium hyaluronate (NaHy) cream preparationand a combination cream preparation comprised of 1.0% sodium hyaluronateand 15.0% urea cream concomitantly three times a day to different areasof her body for three weeks. The woman was evaluated at weeks one, twoand three. The results of this study are reported in the followingtable.

    ______________________________________                                                  Wk. #1     Wk. #2   wk. #3                                          ______________________________________                                        20% Urea  }     1            1      2                                         2% Na Hy  }     0            0      1                                         15% Urea                                                                      +               2            3      4                                         1% NaHy                                                                       ______________________________________                                         Key                                                                           0 = no improvement                                                            1 = slight improvement                                                        2 = moderate improvement                                                      3 = good improvement                                                          4 = excellent improvement                                                

By week four the woman showed excellent improvement by employing thesodium hyaluronate/urea preparation.

The mean level of improvement for the urea preparation over weeks 1-3was 1.33. The mean level of improvement for the sodium hyaluronatepreparation over weeks 1-3 was 0.33. The mean level of improvement forthe combination sodium hyaluronate plus urea over weeks 1-3 was 3.0. Themean level of improvement (3.0) for combined sodium hyaluronate plusurea over weeks 1-3 was 125% greater then the mean level of improvementfor urea over weeks 1-3 (1.33). The mean level of improvement ofcombined sodium hyaluronate plus urea over weeks 1-3 (3.0) was 809%greater then the mean level of improvement for sodium hyaluronate overweeks 1-3 (0.33).

The calculated mean level of improvement for both urea and sodiumhyaluronate over weeks 1-3 was 0.66. The mean level of improvement forcombined sodium hyaluronate plus urea over weeks 1-3 (3.0) was 354%greater then the mean level of improvement for both urea and sodiumhyaluronate over weeks 1-3 (0.66).

The results show a significant increase of therapeutic effect ofcombined sodium hyaluronate plus urea in treating eczema compared toeither urea alone or sodium hyaluronate alone or in considering the meanvalue of their therapeutic effect over the 3 week period.

CLINICAL EVALUATION - 8

In the present study a composition containing sodium hyaluronate plusurea (NAHA+UREA) was employed in the treatment of various ulcers of theskin. Ulcers of the skin including decubitus, diabetic, vascular andAIDS ulcers are commonly seen in a surgical practice. Normally, theseulcers may be treated with debriding agents including saline gauze(wet-to-dry), enzymatics (Elase®, Travase®), whirlpool baths andsurgery. Dressing would include semi-occlusive (Op-Site®, Tagaderm®),occlusive (Restore®, DuoDerm®), hydrogel dressing (Intra-Site®,Geliperm®) and saline gauze. Also, anti-infective agents may be usedincluding Bacitracin®, silver sulfadiazine and Mupirocin®. Many times,the above treatments are unsuccessful and ultimately, surgery must beperformed.

The following was a double-blinded study of 1) combination of sodiumhyaluronate with urea and 2) placebo, in the treatment of various skinulcers.

METHODS

This study comprised eight (8) Case Studies wherein six (6) AIDS ulcers,one (1) decubitus ulcer and one (1) diabetic ulcer were treated with acream containing 2% Sodium Hyaluronate plus 0.5% Urea or a placebocream. The components and preparations of the pharmaceutically activecomposition (NAHA+UREA) was the following:

    ______________________________________                                        Sodium Hyaluronate                                                                             2.0%                                                         Urea             0.5%                                                         Benzyl Alchol    2.0%                                                         Sodium Propionate                                                                              1.5%                                                         Fattibase ®  6.0%                                                         Glycerin         2.0%                                                         Lecithin         2.0%                                                         PEG-4000         2.0%                                                         WFI              ˜80.00%*                                               HCl              ˜2.0%                                                                   100.00%                                                      ______________________________________                                         *(Water for injection) to adjust pH to near normality                    

The placebo (inactive) formula is identical to the active formula withthe exception that 2.50% Carbopol 940 was substituted for the sodiumhyaluronate and urea.

The patients were treated in a double-blinded fashion wherein CaseStudies 1-4 describe treatment with NAHA+UREA cream and Case Studies 5-8describe treatment with a placebo cream.

For all Case Studies, a gentle saline wash was performed at the woundsite and the cream was topically applied twice a day for up to four (4)weeks. A non-occlusive gauze dressing was applied over the wound siteafter the application of the cream. The patients were observedfrequently by the same physician and photographs were taken. Thepatients were to notify the physician if any adverse reactions occurred.

RESULTS

The results of this double-blinded study are presented on a case-by-casebasis as follows:

CASE STUDY 1

(Treatment with 2% Sodium Hyaluronate plus 0.5% Urea Cream)

In Case Study 1 a 34 year old white male juvenile diabetic was treated.This patient had an ulcer approximately 2.5 cm in diameter, Stage 4,extending through the epidermis, dermis, subcutaneous tissue and down tothe periosteum of the lateral malleolus. This ulcer was chronicallyaggravated by the large brace that the patient wore to assist inambulation due to instability of his left ankle and overgrowth of bonytissue. The ulcer had been unresponsive to treatment for over threemonths. The patient had been treated with wet-to-dry saline dressings,Tegaderm®, Duoderm®, Dakin® solution, Bacitracin® ointment and Betadine®wet-to-dry dressings without success. This patient also had undergone apancreas and kidney transplant and was currently on immunosuppressantsand numerous other medications. He suffered from hypertension and tookseveral medications for treatment of that condition. Day 1 showed a 2.5cm in diameter ulcer over the left lateral malleolus. There was edemaand erythema surrounding the ulcer crater. The ulcer extended downthrough the tissue layers to where one could obviously see theperiosteum of the lateral malleolus. Day 10 showed shrinking of theulcer crater and filling in of subcutaneous tissue in the ulcer bed.There was still some edema and erythema in the surrounding tissueplanes. Day 17 showed more narrowing of the ulcer mouth with someclosing of the ends of the ulcer with a yellow amber-like eschar. Thispatient moved away from the study location (out of state) and was unableto come in for a final observation and picture. By telephone he reportedthat the ulcer had closed completely.

CASE STUDY 2

(Treatment with 2% Sodium Hyaluronate plus 0.5% Urea Cream)

In Case Study 2 a 46 year old black male hypertensive AIDS patient wastreated. This patient had two strokes and two episodes of AIDS-relatedpneumonia. He also had one episode of thrush related to his disease. Hehad been treated for over four months by surgeons at a local hospitalfor ulcers of the right lower leg. Debrisan®, Dakin® solution, Betadine®wet-to-dry dressings, saline wet-to-dry dressings, Tegaderm®, Duoderm®,and antibiotic ointments and creams had been utilized to try to healthese ulcers but without success. Day 1 showed the deep ulcer crater wasapproximately 2.0 cm in diameter and located on the anteromedial aspectof the lower one-third of the lower leg. The skin surrounding the ulcerwas hyperpigmented and the ulcer bed was scooped out, containing alllayers of the tissue including the epidermis, dermis, subdermal tissueand down to the periosteum of the bone, which would make it a Stage 4ulcer. Day 7 showed the ulcer decreased in size with filling in of thesubdermal tissue with granulation tissue and some eschar formation atthe edges. Day 14 showed healthy red granulation tissue with the ulcerdecreased in size and totally filled in. Day 28 showed the ulcer healedwith an amber-like eschar forming the scab and some areas of new skinand hypopigmented areas around the previous ulcer crater.

CASE STUDY 3

(Treatment with 2% Sodium Hyaluronate plus 0.5% Urea Cream)

In Case Study 3 a 32 year old white hypertensive male with diabetes wastreated. This diabetic was not insulin dependent. He did have chronicfuruncles and folliculitis along with abscess formation and ulcers ofthe stasis variety. He had a large approximately 3.5 cm in diameterulcer of the left posterior thigh in the upper one-third. The ulcer wasStage 3 extending through the dermis, epidermis and subcutaneous tissue.There was a three (3) inch surrounding area of erythema with some edema.There was no active bleeding from the ulcer or the ulcer bed. Thispatient weighed 648 pounds and had difficulty healing the ulcer due tothe effects of pressure and maintaining a dressing over the area. He hadbeen treated with occlusive dressings including Tegaderm®, salinewet-to-dry dressings, Betadine® wet-to-dry dressings, and Bacitracin®ointment. Day 7 showed healing of the ulcer with decrease in thesurrounding erythema. It appeared that the ulcer was shrinking with ayellowish-amber eschar. There was granulation tissue over the ulcer bed.Day 16 showed the ulcer healed with an amber-like eschar. The scab wasnot a typical sero-sanguinous scab. The erythema had markedly decreasedsurrounding the ulcer itself.

CASE STUDY 4

(Treatment with 2% Sodium Hyaluronate plus 0.5% Urea Cream)

In Case Study 4 the same patient was treated as in Case Study 2 althougha different ulcer was subjected to treatment. Initially there were nothoughts entertained for trying to treat this ulcer because of its largesize, irregularity and the patient's history. Treatment was started oneweek following treatment of the smaller ulcer (of Case Study 2) on theanteromedial aspect of the lower one-third of his lower leg. This CaseStudy 4 ulcer was 8.0×7.0 cm in a rectangular area over the lowerone-third of the anterolateral aspect of his lower leg. This ulcer wouldbe considered as Stage 3 extending through the epidermis and dermis andinto the subcutaneous tissue in the subdermal area. Day 1 showed theulcer with areas involving the subdermal tissue and areas only involvingthe dermis. The surrounding area was hyperpigmented. There was an islandof tissue in the central part of the ulcer that appeared to be fairlynormal but hypopigmented. Day 7 showed some filling in of the subdermalareas and some bridging of the tissue on the perimeter of the ulcer withthe island in the center. There was some granulation tissue present inseveral areas of the ulcer bed. Day 21 showed a marked increase infilling in of the tissue from the ulcer rim to the central tissue islandwith some granulation tissue and some increase in dermal areas. Day 28showed a marked increase in the dermal tissue and filling in of theareas where the subdermal tissue was exposed. New tissue growth wasapparent along with more granulation tissue. The new skin appeared to behypopigmented but solid and connected to that original central tissueisland. At the upper edge of the wound there were some excoriated areaswith some clotted blood due to self infliction by the patient. It shouldbe noted that due to patient compliance there were several gaps in termsof two to three days in the patient's treatment regimen. In some areasone could see the yellow-amber scaling that seems to be typical of ahealing scab when the ulcer healing was almost complete. The patientthought these areas were "bad tissue" and scratched some of them off.

CASE STUDY 5

(Treatment with Placebo Cream)

In Case Study 5 a 41 year old black male AIDS patient was treated. Thepatient had one episode of pneumocystic pneumonia that was previouslytreated. He had a 7.0×9.0 cm. ulcer of the left anteromedial lower legfor six (6) months prior to treatment. The ulcer was a Stage 3 ulcer.The patient stated that he had been treated with Unna boots, silversulfadiazine cream, antibiotic ointments and currently saline wet-to-drydressings on an as necessary basis (p.r.n.). Day 1 showed the largeirregular ulcer which was somewhat circular with extension down into thesubcutaneous tissue. Day 7 showed no change in the ulcer other than whatappeared to be some mechanical debridement along the edges of some of ayellowish exudative material. Day 14 again showed the ulcer with more ofthe subcutaneous tissue missing but no change in the size of the ulcerin terms of shrinkage. The placebo cream was discontinued after Day 14due to lack of progress and because of pain experienced by the patientdue to the frequent dressing changes.

CASE STUDY 6

(Treatment with Placebo Cream)

In Case Study 6 a 36 year old black male was treated, having an AIDSulcer on the left lower leg. The patient had an infected 2.0×4.0 cm.ulcer for over four (4) months. He had been treating the ulcer withantibiotic ointment and band-aids for four (4) months. He most currentlyhad used Bacitracin® ointment with a band-aid type covering. He hadchronic edema of the lower extremity which caused the extremity to bequite enlarged. The edema was nonpitting and woody in consistency. Day 1showed the ulcer, which was a Stage 3 ulcer, extending into the dermallayers and the subcutaneous tissue almost down to the muscle. On Day 7there was no change in the ulcer size and no change in the depth of theulcer or any filling in of the subcutaneous tissue. The patientdiscontinued the use of the placebo cream after eight (8) days due tovery little improvement in the ulcer.

CASE STUDY 7

(Treatment with Placebo Cream)

In Case Study 7 a 43 year old black male AIDS patient was treated,having a large ulcer of the left forearm involving the elbow region. Hedid not have any other health problems. He had been treating this ulcerfor approximately nine (9) months with daily wet-to-dry dressings. Day 1showed a 6.0×7.5 cm. ulcer of the left forearm and elbow area. This wasa Stage 3 ulcer extending down through the subcutaneous tissue. Therewas a foul discharge and odor from the ulcer. On Day 7 it appeared thatthe ulcer was down to the muscle with no decrease in the size of theulcer or filling in of the defect. The patient discontinued use of theplacebo cream after eight (8) days because there was no change in sizeof the ulcer.

CASE STUDY 8

(Treatment with Placebo Cream)

In Case Study 8 a 56 year old black male drug addict with AIDS wastreated. He had been injecting drugs into his arms and legs for overforty (40) years. He suffered from hypertension, but was currently notreceiving any treatment. He also had a borderline diabetic conditionwhich had been neglected. He had a large irregular ulcer of the rightforearm region with an island of normal tissue in the middle of theulcer area. The patient stated that the ulcer had been graduallyincreasing in size despite treatments with Tegaderm®, Duoderm®, Dacon®solution, antibiotic ointments, silver sulfadiazine cream and salinewet-to-dry dressings. Day 1 showed a large butterfly shaped Stage 4ulcer extending down to the subcutaneous tissue just on top of themuscle. There was no odor or discharge from the ulcer. Day 7 showed nosignificant change in the ulcer size with no filling in of the defect.The patient discontinued the use of the placebo cream after twelve (12)days because there was no change in the size of the ulcer.

DISCUSSION

The results of Case Studies 1-4 demonstrated that all of the ulcerstreated with the cream containing 2% Sodium Hyaluronate plus 0.5% Ureashowed dramatic and rapid improvement leading to healing. The use of theNAHA+UREA composition thus provides a significant advancement in thesuccessful treatment of skin ulcers.

The wound healing occurred in much less time than would normally beexpected for the stated degree of severity of the various ulcers.Surprisingly, the ulcers healed with a thin serous scab and not thesero-sanguinous scab as expected. In immunocompromised patients such asthe diabetic with the pancreas and kidney transplant (Case Study 1) andthe AIDS patient (Case Study 2 and 4), the cream was extremely effectivewithout any antibiotic coverage. Those patients treated with the placebocream exhibited no perceptible improvement and, in fact, in all cases,the ulcers began to worsen within three (3) days after the applicationof the placebo cream. Consequently, the placebo cream was applied for nomore than fourteen (14) days on any of the ulcers that were in theplacebo segment of this study. Because of the rapid rate of woundhealing, within five (5) days, patients could be identified who wereusing the NAHA+UREA cream and which patients were using the placebocream. There were no adverse reactions when using the NAHA+UREA cream.The patients using the NAHA+UREA cream expressed their appreciation ofits effectiveness in healing their ulcers when other methods in the pasthad failed.

CLINICAL EVALUATION - 9

In the present study, the same active composition containing sodiumhyaluronate plus the urea (NAHA+UREA) as used in Clinical Evaluation - 8was employed in the treatment of various anorectal disease. TheNAHA+UREA cream was topically applied to the anorectal epithelium andrectal mucosa. Colon and rectal surgeons and gastroenterologiststypically see a large number of anorectal disorders in their practice,including bleeding, irritated hemorrhoids, rectal fissures (either acuteor superficial) and pruritus ani.

This study comprised the treatment of three patients, two with pruritusani and one with a superficial acute rectal fissure. A composition of 2%Sodium Hyaluronate plus 0.5% Urea cream was employed for treatment ofthese anorectal disorders. All three patients were instructed totopically apply the cream 2-3 times per day in the perianal area and tokeep a daily record regarding their symptoms. The patients wereinitially observed by the physician and at the end of two weeks werefinally observed by the physician for evaluation of the treatment.

In all cases, the patients had relief of their symptoms within a rangeof 3-5 days. All three patients rated the NAHA+UREA cream either good orexcellent for relief of their symptoms.

CLINICAL EVALUATION - 10

In the present study the same active composition containing sodiumhyaluronate plus urea (NAHA+UREA) as used in Clinical Evaluation - 8 wasemployed in the treatment of genital lesions and sores caused by theherpes simplex virus.

The study comprised the treatment of five female patients havingmoderate lesions caused by herpes simplex virus. Each patient wasinitially observed by the physician and diagnostic cultures wereperformed which confirmed that four of the five patients had contractedherpes simplex. Each of the patients had vesicular lesions of the vulvawith sharp pain and burning sensations.

A composition of 2% sodium hyaluronate plus 0.5% UREA (NAHA+UREA) creamwas employed for treatment of this herpetic disorder. All five patientswere instructed to topically apply the cream 3-4 times daily to thelesions. The patients were instructed to keep a daily record on a flowsheet regarding their symptoms. Each patient was further instructed touse soap and water to clean the lesions and dry the area with a hairdryer after washing, twice each day. The patients were to apply thecream for a maximum of four days and each was observed from seven to tendays after initial observation.

The results of the study showed that four of the patients indicatedrelief of pain within one to three days. One patient indicated no reliefof pain within four days. On a scale of 1 to 3, four of the patientsrated the cream as a "3" for good relief of pain while the fifth patientrated the cream as a "1" for poor relief of pain. Upon final observationby the physician, all five patients showed no lesions or remnants oflesions.

While only a few exemplary embodiments of this invention have beendescribed in detail, those skilled in the art will recognize that thereare many possible variations and modifications which may be made in theexemplary embodiments while yet retaining many of the novel andadvantageous features of this invention. Accordingly, it is intendedthat the following claims cover all such modifications and variations.

I claim:
 1. A method of treating dermatitis which comprises applying tocutis tissues in need of such treatment a therapeutically effectiveamount of a composition comprising a pharmaceutically acceptablecarrier, urea in an amount of 0.1-40% by weight, and hyaluronic acid ora pharmaceutically acceptable salt thereof in an amount of 0.05-25% byweight.
 2. The method of claim 1 wherein said composition furtherincludes an additive selected from the group consisting of keratolytics,surfactants, counter-irritants, humectants, antiseptics, lubricants,astringents, emulsifiers, wetting agents, wound healing agents,adhesion/coating protectants, vasoconstrictors, anticholinergics,corticosteroids, anesthetics and anti-inflammatory agents.
 3. The methodof claim 1 wherein said composition is in a form selected from the groupconsisting of cream, lotion, gel, ointment, solid, paste, salve, powder,liquid, spray and aerosol.
 4. The method of claim 1 wherein said carrieris water.
 5. The method of claim 1 wherein said pharmaceuticallyacceptable salt is sodium hyaluronate.
 6. The method of claim 1 whereinsaid composition includes urea in an amount of 0.1-30% by weight andhyaluronic acid or a pharmaceutically acceptable salt thereof in anamount of 0.05-15% by weight.
 7. The method of claim 1 wherein saidcomposition includes urea in an amount of 0.5-30% by weight andhyaluronic acid or a pharmaceutically acceptable salt thereof in anamount of 0.1-10% by weight.
 8. The method of claim 1 wherein saidcomposition includes urea in an amount of 1.0-25% by weight andhyaluronic acid or a pharmaceutically acceptable salt thereof in anamount of 0.5-5.0% by weight.